EP0232659A1 - 3-Methyl-substituierte Phenylnaphthyridine und diese enthaltende Arzneimittel - Google Patents

3-Methyl-substituierte Phenylnaphthyridine und diese enthaltende Arzneimittel Download PDF

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Publication number
EP0232659A1
EP0232659A1 EP86402948A EP86402948A EP0232659A1 EP 0232659 A1 EP0232659 A1 EP 0232659A1 EP 86402948 A EP86402948 A EP 86402948A EP 86402948 A EP86402948 A EP 86402948A EP 0232659 A1 EP0232659 A1 EP 0232659A1
Authority
EP
European Patent Office
Prior art keywords
formula
crystals
phenyl
reaction
amino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP86402948A
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English (en)
French (fr)
Other versions
EP0232659B1 (de
Inventor
Jean-Marie Teulon
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
UPSA SAS
Original Assignee
Carpibem SA
UPSA SAS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from FR8600102A external-priority patent/FR2592649B1/fr
Priority claimed from FR8600104A external-priority patent/FR2592651B1/fr
Application filed by Carpibem SA, UPSA SAS filed Critical Carpibem SA
Priority to AT86402948T priority Critical patent/ATE66479T1/de
Publication of EP0232659A1 publication Critical patent/EP0232659A1/de
Application granted granted Critical
Publication of EP0232659B1 publication Critical patent/EP0232659B1/de
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to phenyl-naphthyridines of formula (I). It also relates to the process for the preparation of said products and their applications, in particular in therapy.
  • this substitution when it is CH3, SCH3, CN, CH2CN or CONH2, must be located in meta position, when it is Cl, it can be in position meta or para, whereas when it is F, it can be in the meta, ortho or para position.
  • the two substituents of the aromatic ring are F; in this case, the three combinations 2,6 2,5, and 2,4 are possible but the positions 2,5 and 2,4 are preferable.
  • the 3-CN 4-halogen (F or Cl) combination is also particularly desirable.
  • the compounds of formula (I) according to the invention can be synthesized: - either by a Réformatsky reaction followed by dehydration, - either by a Wittig reaction followed by a cyclization, - either by a Perkin reaction, - either by a Claisen reaction, on an aldehyde of formula (II): in formula (II), X, Y and Z are defined as above.
  • the aldehydes of formula (II) can be obtained, by oxidation of an alcohol of formula (III) using a mild oxidant such as for example MnO2, in an organic solvent such as dichloromethane or chloroform, at a temperature between 20 and 50 ° C.
  • a mild oxidant such as for example MnO2
  • an organic solvent such as dichloromethane or chloroform
  • the alcohols of formula (III) are obtained by conventional reduction such as for example with double aluminum and lithium hydride in an organic solvent such as for example the tetrahydrofuran of an acid or one of its esters of formula (IV).
  • an organic solvent such as for example the tetrahydrofuran of an acid or one of its esters of formula (IV).
  • the reduction of the ester will be chosen by a reducing agent respecting this substitution, for example lithium borohydride prepared "a situ" from potassium borohydride and lithium chloride.
  • X, Y and Z are defined as above.
  • R3 is a hydrogen atom or an alkyl.
  • the industrially preferred process for the synthesis of products of formula (I) consists in the use of the known Perkin reaction by which an aldehyde of formula (II) is reacted with an anhydride of formula: in the presence of the sodium salt of the corresponding acid.
  • the reaction can be carried out without solvent or in a solvent such as methylpyrrolidone at a temperature of approximately 100 to 200 ° C.
  • n 1: propionic anhydride and sodium pripionate.
  • compositions useful in particular for the treatment of gastrointestinal ulcers, characterized in that they contain, in association with an acceptable excipient, at least one compound of formula (I).
  • a solution of 10 g of (3-cyano-phenyl) 2-amino-nicotinaldehyde prepared in Example 3, 20 ml of propionate and 20 ml of ethanol containing 0.054 mol of ethyl ethylate are stirred at ambient temperature for 4 h.
  • sodium prepared by adding 1.25 g of sodium in 20 ml of ethanol.
  • reaction mixture is then cooled, added with water and ice and then neutralized with a bicarbonate solution. sodium.
  • the crystals formed are drained, washed with water and dried.
  • recrystallization from the acetonitrile-dimethylformamide mixture 6.3 g of (4-hydroxyphenyl) -1 dihydro-1,2-2-oxo-methyl-3-naphthyridine-1,8 is recovered in the form of crystals of melting point 308 ° C.
  • a medicinal ulcerogenic agent or a necrotizing agent absolute ethanol
  • a necrotizing agent absolute ethanol
  • the stomachs are then removed according to the test, respectively 6 h and 1 h after the last treatment. Gastric lesions are then assessed macroscopically (scoring and measuring the size of the ulcers).
  • results are expressed in the form of active doses 50 (dose inhibiting by 50% the lesions caused) determined graphically from the right expressing the relationship between the percentages of inhibition and the doses used.
  • Ligation at the pylorus is performed under ether anesthesia in batches of 5 male rats of OFA strain (from IFFA CREDO, France) weighing 180-200 g.
  • the product to be studied is administered subcutaneously at the time of ligation.
  • the animals are sacrificed 4 h later and the gastric liquid is collected then its acidity titrated with 0.1N soda at pH 4 and 7.
  • results are expressed in active doses 50 (dose causing an inhibition of 50% of the total acid secretion) determined graphically from the right expressing the percentage of inhibition of the total acid secretion according to the doses used.
  • Example 5 (expressed in mg.kg-1, subcutaneous administration) Example 5 0.038 Example 8 0.045 Example 9 0.040 Example 13 0.050 Example 17 0.064
  • They can be used by injection or orally in the treatment of peptic ulcers, in the form of ampoules for injection of tablets or capsules dosed from 5 to 100 mg.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pyridine Compounds (AREA)
EP86402948A 1986-01-06 1986-12-29 3-Methyl-substituierte Phenylnaphthyridine und diese enthaltende Arzneimittel Expired - Lifetime EP0232659B1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT86402948T ATE66479T1 (de) 1986-01-06 1986-12-29 3-methyl-substituierte phenylnaphthyridine und diese enthaltende arzneimittel.

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
FR8600102A FR2592649B1 (fr) 1986-01-06 1986-01-06 Cyano et amido phenyl-naphtyridines, leur procede de preparation, medicaments les contenant, notamment anti-ulceres.
FR8600102 1986-01-06
FR8600104 1986-01-06
FR8600104A FR2592651B1 (fr) 1986-01-06 1986-01-06 Nouvelles phenyl naphtyridines comportant un substituant methyle en position 3, et les medicaments qui en contiennent.

Publications (2)

Publication Number Publication Date
EP0232659A1 true EP0232659A1 (de) 1987-08-19
EP0232659B1 EP0232659B1 (de) 1991-08-21

Family

ID=26224940

Family Applications (1)

Application Number Title Priority Date Filing Date
EP86402948A Expired - Lifetime EP0232659B1 (de) 1986-01-06 1986-12-29 3-Methyl-substituierte Phenylnaphthyridine und diese enthaltende Arzneimittel

Country Status (12)

Country Link
US (1) US4786642A (de)
EP (1) EP0232659B1 (de)
KR (1) KR900004587B1 (de)
AT (1) ATE66479T1 (de)
AU (1) AU591746B2 (de)
DE (1) DE3681015D1 (de)
DK (1) DK2687A (de)
ES (1) ES2037666T3 (de)
GR (1) GR3003107T3 (de)
NZ (1) NZ218773A (de)
PH (1) PH23268A (de)
PT (1) PT84048B (de)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0267691A2 (de) * 1986-10-15 1988-05-18 Schering Corporation Verwendung von 1-substituierten Naphthyridin- und Pyridopyrazinderivaten für die Herstellung von Immunosuppressoren-arzneimittel.
US4775686A (en) * 1986-10-15 1988-10-04 Schering Corporation Naphthyridine derivatives and method for treating allergic reactions
US4916131A (en) * 1986-10-15 1990-04-10 Schering Corporation Naphthyridine derivatives and method for treating allergic reactions
US5037826A (en) * 1986-10-15 1991-08-06 Schering Corporation 1-substituted naphthyridine and pyridopyrazine derivatives
EP0900789A3 (de) * 1997-08-29 2000-02-02 SSP Co., Ltd. Substituierte Chinolon-Derivate und diese enthaltende Pharmazeutika
WO2007123939A2 (en) * 2006-04-19 2007-11-01 Laboratoires Serono S.A. Novel arylamino n-heteraryls as mek inhibitors

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ218774A (en) * 1986-01-06 1990-06-26 Carpibem 3-substituted phenylnaphthyridines and pharmaceutical compositions
FR2607506B1 (fr) * 1986-12-02 1989-01-06 Rhone Poulenc Sante Nouveaux derives de l'isoindolinone, leur preparation et les compositions pharmaceutiques qui les contiennent
US5760034A (en) * 1990-11-30 1998-06-02 Schering Corporation Heterocyclic substituted naphthyridinones and methods and compositions employing them
FR2706898B1 (de) * 1993-06-25 1995-09-08 Union Pharma Scient Appl
GB9507224D0 (en) * 1995-04-07 1995-05-31 Merck Sharp & Dohme Therapeutic agents
US5994367A (en) 1997-03-07 1999-11-30 The University Of North Carolina At Chapel Hill Method for treating tumors using 2-aryl-naphthyridin-4-ones
EP1403270A4 (de) * 2001-06-12 2006-11-02 Grelan Pharmaceutical Co Pde-iv-inhibitoren

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4128649A (en) * 1977-06-29 1978-12-05 Sandoz, Inc. 4-Hydroxy-pyrido[2,3-b]pyridine-2(1H)-one-3-carboxylic acids and esters
EP0000490A1 (de) * 1977-07-18 1979-02-07 Merck & Co. Inc. Substituierte Naphthyridinone, Verfahren zu ihrer Herstellung und therapeutische Verwendungen
US4215123A (en) * 1979-05-07 1980-07-29 American Home Products Corporation Antisecretory 4-oxy-3-carboxy or cyano-1,2-dihydro-2-oxo-1,8-naphthyridine derivatives
EP0018735A1 (de) * 1979-04-18 1980-11-12 American Home Products Corporation 1,8-Naphthyridin-Derivate, ihre Herstellung, sie enthaltende pharmazeutische Zusammensetzungen
EP0172058A1 (de) * 1984-07-11 1986-02-19 Laboratoires Upsa Phenylnaphthyridine, Verfahren zu deren Herstellung, diese enthaltende Arzneimittel, insbesondere Antigeschwür

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ218774A (en) * 1986-01-06 1990-06-26 Carpibem 3-substituted phenylnaphthyridines and pharmaceutical compositions

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4128649A (en) * 1977-06-29 1978-12-05 Sandoz, Inc. 4-Hydroxy-pyrido[2,3-b]pyridine-2(1H)-one-3-carboxylic acids and esters
EP0000490A1 (de) * 1977-07-18 1979-02-07 Merck & Co. Inc. Substituierte Naphthyridinone, Verfahren zu ihrer Herstellung und therapeutische Verwendungen
EP0018735A1 (de) * 1979-04-18 1980-11-12 American Home Products Corporation 1,8-Naphthyridin-Derivate, ihre Herstellung, sie enthaltende pharmazeutische Zusammensetzungen
US4215123A (en) * 1979-05-07 1980-07-29 American Home Products Corporation Antisecretory 4-oxy-3-carboxy or cyano-1,2-dihydro-2-oxo-1,8-naphthyridine derivatives
EP0172058A1 (de) * 1984-07-11 1986-02-19 Laboratoires Upsa Phenylnaphthyridine, Verfahren zu deren Herstellung, diese enthaltende Arzneimittel, insbesondere Antigeschwür

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0267691A2 (de) * 1986-10-15 1988-05-18 Schering Corporation Verwendung von 1-substituierten Naphthyridin- und Pyridopyrazinderivaten für die Herstellung von Immunosuppressoren-arzneimittel.
US4775686A (en) * 1986-10-15 1988-10-04 Schering Corporation Naphthyridine derivatives and method for treating allergic reactions
EP0267691A3 (de) * 1986-10-15 1989-08-23 Schering Corporation Verwendung von 1-substituierten Naphthyridin- und Pyridopyrazinderivaten für die Herstellung von Immunosuppressoren-arzneimittel.
US4916131A (en) * 1986-10-15 1990-04-10 Schering Corporation Naphthyridine derivatives and method for treating allergic reactions
US5037826A (en) * 1986-10-15 1991-08-06 Schering Corporation 1-substituted naphthyridine and pyridopyrazine derivatives
EP0900789A3 (de) * 1997-08-29 2000-02-02 SSP Co., Ltd. Substituierte Chinolon-Derivate und diese enthaltende Pharmazeutika
WO2007123939A2 (en) * 2006-04-19 2007-11-01 Laboratoires Serono S.A. Novel arylamino n-heteraryls as mek inhibitors
WO2007123939A3 (en) * 2006-04-19 2007-12-21 Applied Research Systems Novel arylamino n-heteraryls as mek inhibitors
US7772233B2 (en) 2006-04-19 2010-08-10 Merck Serono, S.A. Arylamino N-heteroaryl compounds as MEK inhibitors
US8802703B2 (en) 2006-04-19 2014-08-12 Merck Serono S.A. Arylamino N-heteraryl compounds as MEK inhibitors

Also Published As

Publication number Publication date
DE3681015D1 (de) 1991-09-26
US4786642A (en) 1988-11-22
DK2687A (da) 1987-07-07
PT84048A (fr) 1987-02-01
DK2687D0 (da) 1987-01-05
ATE66479T1 (de) 1991-09-15
NZ218773A (en) 1990-05-28
KR900004587B1 (ko) 1990-06-30
GR3003107T3 (en) 1993-02-17
AU591746B2 (en) 1989-12-14
KR870007166A (ko) 1987-08-17
EP0232659B1 (de) 1991-08-21
ES2037666T3 (es) 1993-07-01
PH23268A (en) 1989-06-23
AU6702286A (en) 1987-07-09
PT84048B (pt) 1989-02-28

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